1. Field of the Invention
The present invention relates generally to monomeric forms of aminoacyl-tRNA synthetase (AARS) polypeptides, compositions comprising such polypeptides, and methods of using same.
2. Description of the Related Art
Aminoacyl-tRNA synthetases, which catalyze the aminoacylation of tRNA molecules, are essential for decoding genetic information during the process of translation. In higher eukaryotes, aminoacyl-tRNA synthetases associate with other polypeptides to form supramolecular multienzyme complexes. Each of the eukaryotic tRNA synthetases consists of a core enzyme, which is closely related to the prokaryotic counterpart of the tRNA synthetase, and an additional domain that is appended to the amino-terminal or carboxyl-terminal end of the core enzyme. Human tyrosyl-tRNA synthetase (YRS), for example, has a carboxyl-terminal domain that is not part of prokaryotic and lower eukaryotic YRS molecules.
Several aminoacyl-tRNA synthetases have been demonstrated to have non-canonical functions distinct from their involvement in translation. For example, mini-tyrosyl tRNA synthetase (mini-YRS), the N-terminal domain of YRS which corresponds to amino acid residues 1-364 and is cleaved by polymorphonuclear cell elastase and plasmin, is a member of the aminoacyl tRNA synthetase “AARS” multifunction cytokine-like proteins and peptides. In vitro, mini-YRS has been shown to stimulate neutrophil activation and chemotaxis, endothelial cell proliferation and migration, and is pro-angiogenic in chick chorioallantoic membrane (CAM) and mouse matrigel assays. Mini-YRS has an ELR motif that, like CXC-chemokines such as IL-8, confers its chemokine and angiogenic activities. Like other ELR-containing cytokines, mutation of this motif inhibits mini-YRS binding and stimulation of leukocytes and angiogenesis.
In addition, truncated forms or WRS have been demonstrated to have angiogenic properties. In normal human cells, there are two forms of WRS that can be detected: a major form consisting of the full-length molecule (amino acid residues 1-471) and a minor truncated form. The minor form is generated by the deletion of an amino-terminal domain through alternative splicing of the pre-mRNA. The amino-terminus of mini-WRS has been determined to be the methionine residue at position 48 of the full-length WRS molecule. Alternatively, truncated WRS can be generated by proteolysis. For example, bovine WRS is highly expressed in the pancreas and is secreted into the pancreatic juice, thus resulting in the production of a truncated WRS molecule. Additional studies indicate that mini-WRS inhibits VEGF-induced cell proliferation and migration (Wakasugi et al., Proc. Natl. Acad. Sci. 99: 173-177 (2002)). In particular, a chick CAM assay shows that mini WRS blocks angiogenic activity of VEGF. In contrast, the full-length WRS does not inhibit angiogenesis. Thus, removal of the first 48 amino acid residues exposes the anti-angiogenic activity of WRS. Therefore, as with YRS, certain forms of WRS possess activities other than the aminoacylation of tRNA.
Given these observations of non-canonical and therapeutically relevant activities associated alternative forms of YRS and WRS, there is a need to identify biologically relevant forms and/or activities of other aminoacyl-tRNA synthetase proteins in order to exploit the full therapeutic potential of this family of proteins. Accordingly, the present invention addresses these needs and offers other related advantages.